A subject of the present invention is new derivatives of N-(iminomethyl)amines comprising the aminodiphenylamine, oxodiphenylamine, carbazole, phenazine, phenothiazine, phenoxazine or oxodiphenyl unit in their skeleton. These derivatives have an inhibitory activity on NO-synthase enzymes producing nitrogen monoxide NO and/or an activity which traps the reactive oxygen species (ROS). The invention relates to the derivatives corresponding to general formula (I) defined below, their preparation methods, the pharmaceutical preparations containing them and their use for therapeutic purposes, in particular their use as NO-synthase inhibitors and selective or non selective traps for reactive oxygen species.
Given the potential role of NO and the ROS""s in physiopathology, the new derivatives described corresponding to general formula (I) may produce beneficial or favourable effects in the treatment of pathologies where these chemical species are involved. In particular:
Proliferative and inflammatory diseases such as for example atherosclerosis, pulmonary hypertension, respiratory distress, glomerulonephritis, portal hypertension, psoriasis, arthrosis and rheumatoid arthritis, fibroses, angiogenisis, amyloidoses, inflammations of the gastro-intestinal system (ulcerous or non-ulcerous colitis, Crohn""s disease), diarrhoea.
Diseases affecting the pulmonary system and airways (asthma, sinusitis, rhinitis).
Cardio-vascular and cerebro-vascular disorders including for example, migraine, arterial hypertension, septic shock, ischemic or hemorragic, cardiac or cerebral infarctions, ischemias and thromboses.
Disorders of the central or peripheral nervous system such as for example neurodegenerative diseases where there can in particular be mentioned cerebral infarctions, sub-arachnoid haemorrhaging, ageing, senile dementias including Alzheimer""s disease, Huntington""s chorea, Parkinson""s disease, Creutzfeld Jacob disease and prion diseases, amyotrophic lateral sclerosis; ocular neuropathies such as glaucoma but also pain, cerebral and bone marrow traumas, addiction to opiates, alcohol and addictive substances, cognitive disorders, encephalopathies, encephalopathies of viral or toxic origin.
Disorders of the skeletal muscle and neuromuscular joints (myopathy, myosis) as well as cutaneous diseases.
Cataracts.
Organ transplants.
Auto-immune and viral diseases such as for example lupus, AIDS, parasitic and viral infections, diabetes and its complications, multiple sclerosis.
Cancer.
Neurological diseases associated with intoxications (Cadmium poisoning, inhalation of n-hexane, pesticides, herbicides), associated with treatments (radiotherapy) or disorders of genetic origin (Wilson""s disease).
all the pathologies characterized by an excessive production or dysfunction of NO and/or ROS""s.
In all these pathologies, there is experimental evidence demonstrating the involvement of NO or ROS""s (J. Med. Chem. (1995) 38, 4343-4362; Free Radic. Biol. Med. (1996) 20, 675-705; The Neuroscientist (1997) 3, 327-333).
Moreover, in earlier patents, the inventors have already described NO Synthase inhibitors and their use (U.S. Pat. Nos. 5,081,148; 5,360,925) and more recently the combination of these inhibitors with products having antioxidant or antiradicular properties (Patent Application PCT WO/09653). They have also described in not yet published Applications other derivatives of amidines or, more recently, derivatives of aminopyridines. These derivatives of amidines or aminopyridines have the characteristic of being both NO Synthase inhibitors and ROS inhibitors.
A subject of the present invention is new derivatives of amidines, their preparation and their use in therapeutics.
The compounds of the invention correspond to general formula (I): 
in which
"PHgr" represents a bond or a phenylene radical which can include, in addition to the two chains already represented in general formula (I), up to two substituents chosen from a hydrogen atom, a halogen, an OH group, and a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms;
A represents a 
xe2x80x83radical in which R1, R2, R3, R4, R5 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or a cyano, nitro or NR6R7 radical,
R6 and R7 representing, independently, a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or also a xe2x80x94COR8 group,
R8 representing a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or NR9R10,
R9 and R10 representing, independently, a hydrogen atom, the OH group or a linear or branched alkyl radical having 1 to 6 carbon atoms,
R11 representing a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or a xe2x80x94COR12 radical,
and R12 representing a hydrogen atom, the OH group, a linear or branched alkyl radical having 1 to 6 carbon atoms, or a 
xe2x80x83radical in which R1, R2, R3, R4, R5 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or a cyano, nitro or NR6R7 radical,
R6 and R7 representing, independently, a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or also a xe2x80x94COR8 group,
R8 representing a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or NR9R10,
R9 and R10 representing, independently, a hydrogen atom, the OH group or a linear or branched alkyl radical having 1 to 6 carbon atoms,
B represents xe2x80x94CH2xe2x80x94NO2, a linear or branched alkyl radical having 1 to 6 carbon atoms, carbocyclic or heterocyclic aryl with 5 or 6 members containing 1 to 4 heteroatoms chosen from O, S, N and in particular the thiophene, furan, pyrrole or thiazole radical, the aryl radical being optionally substituted by one or more groups chosen from linear or branched alkyl, alkenyl or alkoxy radicals having 1 to 6 carbon atoms, or B represents an NR13R14 radical, in which R13 and R14 representing, independently, a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms or a cyano or nitro radical, or R13 and R14 form with the nitrogen atom a non aromatic heterocycle with five to six members, the elements of the chain being chosen from a group composed of xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94;
W does not exist, or represents a bond, or O, S or NR15, in which R15 represents a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms;
X represents a bond or a (CH2)kxe2x80x94NR16xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94NR16xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NR16xe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94NR16xe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94NR16xe2x80x94COxe2x80x94NR17xe2x80x94 radical, k representing 0 or 1;
Y represents a bond or a radical chosen from the xe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)mxe2x80x94Oxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94NR18xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94NR18xe2x80x94COxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94COxe2x80x94NR18xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94Qxe2x80x94(CH2)nxe2x80x94 radicals,
Q representing piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-oxypiperidine or 4-aminopiperidine radicals, m and n being integers from 0 to 6;
R16, R17 and R18 represent, independently, a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms;
or are salts of the products mentioned previously.
By linear or branched alkyl having 1 to 6 carbon atoms, is meant in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals. By linear or branched alkoxy having 1 to 6 carbon atoms, is meant the alkyl radical of which has the meaning indicated previously. Finally, by halogen, is meant fluorine, chlorine, bromine or iodine atoms.
Preferably, the compounds according to the invention are the compounds of general formula (I) such that:
A represents a 
xe2x80x83radical in which R1, R2, R3, R4, R5 represent, independently, a hydrogen atom, the OH group or a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, R11 representing a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms, or a 
xe2x80x83radical in which R1, R2, R3, R4, R5 represent, independently, a hydrogen atom, the OH group or a linear or branched alkyl oralkoxy radical having 1 to 6 carbon atoms;
B represents a carbocyclic or heterocyclic aryl radical with 5 or 6 members containing 1 to 4 heteroatoms chosen from O, S, N and in particular the thiophene, furan, pyrrole or thiazole radicals, the aryl radical being optionally substituted by one or more groups chosen from linear or branched alkyl, alkenyl or alkoxy radicals having 1 to 6 carbon atoms;
W does not exist, or represents a bond, S or NR15, in which R15 represents a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms;
X represents a bond or a xe2x80x94(CH2)kxe2x80x94NR16xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94NR16xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NR16xe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94NR16xe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94NR16xe2x80x94COxe2x80x94NR17xe2x80x94 radical k representing 0 or 1;
Y represents a bond or a radical chosen from the xe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)mxe2x80x94Oxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94NR18xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94NR18xe2x80x94COxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94COxe2x80x94NR18xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94Qxe2x80x94(CH2)nxe2x80x94 radicals,
Q representing piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-oxypiperidine or 4-aminopiperidine, m and n being integers from 0 to 6;
or are salts of the products mentioned previously.
More preferentially, the compounds according to the invention are compounds of general formula (I) such that:
A represents a 
xe2x80x83radical in which R1, R2, R3, R4 and R5 represent, independently, a hydrogen atom, the OH group or a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, R11 representing a hydrogen atom or a methyl radical, or a 
xe2x80x83radical in which R1, R2, R3, R4, R5 represent, independently, a hydrogen atom, the OH group or a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms;
B represents one of the phenyl, thiophene, furan, pyrrole or thiazole radicals optionally substituted by one or more groups chosen from linear or branched alkyl, alkenyl or alkoxy radicals having 1 to 6 carbon atoms;
W does not exist, or represents a bond, S or NR15, in which R15 represents a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms;
X represents a bond or a xe2x80x94(CH2)kxe2x80x94NR16xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94NR16xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NR16xe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94NR16xe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94NR16xe2x80x94COxe2x80x94NR17xe2x80x94 radical, k representing 0 or 1;
Y represents a bond or a radical chosen from the xe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)mxe2x80x94Oxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94NR18xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94NR18xe2x80x94COxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94COxe2x80x94NR18xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94Qxe2x80x94(CH2)nxe2x80x94 radicals,
Q representing piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-oxypiperidine or 4-aminopiperidine, m and n being integers comprised from 0 to 6;
or are salts of the products mentioned previously.
Yet more preferentially, the compounds according to the invention are compounds of general formula (I) such that:
A represents a 
xe2x80x83radical in which R1, R2, R3, R4, R5 represent, independently, a hydrogen atom or a methyl radical, R11 representing a hydrogen atom or a methyl radical;
B represents the thiophene radical;
W does not exist, represents a single bond or S;
X represents a bond or represents a xe2x80x94(CH2)kxe2x80x94NR16xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94NR16xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NR16xe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94NR16xe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94NR16xe2x80x94COxe2x80x94NR17xe2x80x94 radical; k representing 0 or 1; Y represents a bond or a radical chosen from the xe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)mxe2x80x94Oxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94NR18xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94NR18xe2x80x94COxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94COxe2x80x94NR18xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94Qxe2x80x94(CH2)nxe2x80x94 radicals,
Q representing piperazine, m and n being integers comprised between 0 and 6;
R16, R17 and R18 represent a hydrogen atom;
or are salts of the products mentioned previously.
Quite particularly preferred are the following compounds described in the examples:
N-[4-(phenylamino)phenyl]-2-thiophenecarboximidamide;
4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzeneacetamide;
{4-{[2-thienyl(imino)methyl]amino}phenoxy}-N-[4-(phenylamino)phenyl]-acetamide;
4-{[2-thienyl(imino)methyl]amino}-N-[2-(phenylamino)phenyl]-benzenebutanamide;
4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzenebutanamide;
4-{[2-thienyl(imino)methyl]amino}-N-[4-(4-methoxyphenylamino)phenyl]-benzenebutanamide;
2-{4-{[2-thienyl(imino)methyl]amino}phenyl}-ethyl[4-(phenylamino)phenyl]-carbamate;
N-{2-{4-{[2-thienyl(imino)methyl]amino}phenyl}ethyl}-Nxe2x80x2-[4-(phenylamino)phenyl]-urea;
4-{4-{[2-thienyl(imino)methyl]amino}phenyl}-N-[4-(phenylamino)phenyl]-1-piperazine-acetamide;
1-{[(4-phenylamino)phenylamino]carbonyl}-4-{4-{[2-thienyl(imino)methyl]amino}phenyl}-piperazine;
4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzenebutanamine;
3-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzenepropanamide;
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(4-toluidino)phenyl]butanamide;
4-anilinophenyl-4-(4-{[amino(2-thienyl)methylidene]amino}-phenyl)butanoate;
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(4-toluidino)phenyl]butanamide;
Nxe2x80x2-{4-[4-(3-anilinophenoxy)butyl]phenyl}-2-thiophenecarboximidamnide;
Nxe2x80x2-(9H-carbazol-3-yl)-2-thiophenecarboximidamide;
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(9H-carbazol-3-yl)butanamide;
Nxe2x80x2-[4-(10H-phenothiazin-2-yloxy)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-{4-[(10-methyl-10H-phenothiazin-2-yl)oxy]phenyl}-2-thiophenecarboximidamide;
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(10H-phenothiazin-3-yl)butanamide;
Nxe2x80x2-(4-{4-[2-(10H-phenothiazin-2-yloxy)ethyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamide;
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[4-(4-toluidino)phenyl]butanamide;
3-anilinophenyl 4-(4-{[amino(2-thienyl)methylidene]amino}-phenyl)butanoate;
2-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(9H-carbazol-4-yloxy)ethyl]acetamide;
N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-2-anilinobenzamide;
N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-2-(2,3-dimethylanilino)benzamide;
Nxe2x80x2-{4-[4-(2-anilinobenzoyl)-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;
Nxe2x80x2-(4-{4-[2-(2,3-dimethylanilino)benzoyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamide;
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(4-phenoxyphenyl)butanamide;
N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-4-(4-hydroxyphenoxy)benzamide;
N-[2-(9H-carbazol-4-yloxy)ethyl]-2-thiophenecarboximidamide;
N-[3-(9H-carbazol-4-yloxy)propyl]-2-thiophenecarboximidamide;
N-{4-[4-(10H-phenothiazin-2-yloxy)butyl]phenyl}-2-thiophenecarboximidamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-(4-anilinophenyl)propanamide;
Nxe2x80x2-(4-{2-[(10H-phenothiazin-3-ylmethyl)amino]ethyl}phenyl)-2-thiophenecarboximidamide;
N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-2-methoxy-10H-phenothiazine-1-carboxamide;
Nxe2x80x2-[4-(2-{[(2-methoxy-10H-phenothiazin-1-yl)methyl]amino}ethyl)phenyl]-2-thiophenecarboximidamide;
Nxe2x80x2-{4-[(10H-phenothiazin-2-yloxy)methyl]phenyl}-2-thiophenecarboximidamide;
or their salts.
Among the exemplified compounds, the following compounds are in particular preferred:
{4-{[2-thienyl(imino)methyl]amino}phenoxy}-N-[4-(phenylamino)phenyl]-acetamide;
4-{[2-thienyl(imino)methyl]amino}-N-[2-(phenylamino)phenyl]-benzenebutanamide;
4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzenebutanamide;
2-{4-{[2-thienyl(imino)methyl]amino}phenyl}-ethyl[4-(phenylamino)phenyl]-carbamate;
4-{4-{[2-thienyl(imino)methyl]amino}phenyl}-N-[4-(phenylamino)phenyl]-1-piperazine-acetamide;
3-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzenepropanamide;
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-[2-(4-toluidino)phenyl]butanamide;
Nxe2x80x2-{4-[4-(3-anilinophenoxy)butyl]phenyl}-2-thiophenecarboximidamide;
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(9H-carbazol-3-yl)butanamide;
Nxe2x80x2-[4-(10H-phenothiazin-2-yloxy)phenyl]-2-thiophenecarboximidamide;
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(10H-phenothiazin-3-yl)butanamide;
Nxe2x80x2-(4-{4-[2-(10H-phenothiazin-2-yloxy)ethyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamide;
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(4-phenoxyphenyl)butanamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-(4-anilinophenyl)propanamide;
Nxe2x80x2-(4-{2-[(10H-phenothiazin-3-ylmethyl)amino]ethyl}phenyl)-2-thiophenecarboximidamide;
N-(4-{[amino(2-thienyl)methylidene]amino}phenethyl)-2-methoxy-10H-phenothiazine-1-carboxamide;
or their salts.
Also more particularly the following compounds are preferred:
4-{[2-thienyl(imino)methyl]amino}-N-[2-(phenylamino)phenyl]-benzenebutanamide;
4-{[2-thienyl(imino)methyl]amino}-N-[4-(phenylamino)phenyl]-benzenebutanamide;
Nxe2x80x2-[4-(10H-phenothiazin-2-yloxy)phenyl]-2-thiophenecarboximidamide;
4-(4-{[amino(2-thienyl)methylidene]amino}phenyl)-N-(10H-phenothiazin-3-yl)butanamide;
3-[(3-{[amino(2-thienyl)methylidene]amino}-benzyl)amino]-N-(4-anilinophenyl)propanamide;
Nxe2x80x2-(4-{2-[(10H-phenothiazin-3-ylmethyl)amino]ethyl}phenyl)-2-thiophenecarboximidamide;
or their salts.
In a general manner, the compounds of general formula (I) in which X represents a bond or one of the xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94NR16xe2x80x94, xe2x80x94NR16xe2x80x94COxe2x80x94 or xe2x80x94NR16xe2x80x94COxe2x80x94Oxe2x80x94 radicals and Y represents one of the (CH2)m or xe2x80x94(CH2)mxe2x80x94NR18xe2x80x94(CH2)nxe2x80x94 radicals will be preferred.
In certain cases, the compounds according to the present invention can contain asymmetrical carbon atoms. As a result, the compounds according to the present invention have two possible enantiomeric forms, i.e. xe2x80x9cRxe2x80x9d and xe2x80x9cSxe2x80x9d configurations. The present invention includes the two enantiomeric forms and all combinations of these forms, including the racemic xe2x80x9cRSxe2x80x9d mixtures. In an effort to simplify matters, when no specific configuration is indicated in the structural formulae, it should be understood that the two enantiomeric forms and their mixtures are represented.
The invention further relates, as new industrial products, to the synthesis intermediates of general formula (IS), useful for the preparation of products of general formula (I) defined above,
Axe2x80x94Xxe2x80x94Yxe2x80x94"PHgr"xe2x80x94Txe2x80x83xe2x80x83(IS)
general formula (IS) in which
A represents a 
xe2x80x83radical in which R1, R2, R3, R4, R5 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or a cyano, nitro or NR6R7 radical,
R6 and R7 representing, independently, a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or also a xe2x80x94COR8 group,
R8 representing a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or NR9R10,
R9 and R10 representing, independently, a hydrogen atom, the OH group or a linear or branched alkyl radical having 1 to 6 carbon atoms,
R11 representing a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or a xe2x80x94COR12 radical,
and R12 representing a hydrogen atom, the OH group, a linear or branched alkyl radical having 1 to 6 carbon atoms, or a 
xe2x80x83radical in which R1, R2, R3, R4, R5 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or a cyano, nitro or NR6R7 radical,
R6 and R7 representing, independently, a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or also a xe2x80x94COR8 group,
R8 representing a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or NR9R10,
R9 and R10 representing, independently, a hydrogen atom, the OH group or a linear or branched alkyl radical having 1 to 6 carbon atoms;
W does not exist, or represents a bond, or O, S or NR15, in which R15 represents a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms;
X represents a bond or a xe2x80x94(CH2)kxe2x80x94NR16xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94NR16xe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94NR16xe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94NR16xe2x80x94COxe2x80x94Oxe2x80x94 or xe2x80x94NR16xe2x80x94COxe2x80x94NR17xe2x80x94 radical, k representing 0 or 1;
Y represents a bond or a radical chosen from the xe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)mxe2x80x94Oxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94Sxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94NR18xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94NR18xe2x80x94COxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94NR18xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)mxe2x80x94Qxe2x80x94(CH2)nxe2x80x94 radicals,
Q representing piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-oxypiperidine or 4-aminopiperidine, m and n being integers from 0 to 6;
"PHgr" represents a bond or a phenylene radical which may comprise, in addition to the two chains already represented in general formula (I), up to two substituents chosen from a hydrogen atom, a halogen, an OH group and a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms;
T represents NO2or NH2;
R16, R17 and R18 represent, independently, a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms.
The invention further relates, as new industrial products, to the synthesis intermediates of general formula (ISxe2x80x2), useful for the preparation of products of general formula (I) in which X represents the xe2x80x94NR16xe2x80x94COxe2x80x94 radical and Y represents the (CH2)mxe2x80x94NR18xe2x80x94(CH2)nxe2x80x94 radical, 
general formula (ISxe2x80x2) in which
A represents a 
xe2x80x83radical in which R1, R2, R3, R4 and R5 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or a cyano, nitro or NR6R7 radical,
R6 and R7 representing, independently, a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or also a xe2x80x94COR8 group,
R8 representing a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or NR9R10,
R9 and R10 representing, independently, a hydrogen atom, the OH group, a linear or branched alkyl radical having 1 to 6 carbon atoms,
R11 representing a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or also a xe2x80x94COR12 radical,
and R12 representing a hydrogen atom, the OH group, a linear or branched alkyl radical having 1 to 6 carbon atoms, or a 
xe2x80x83radical in which R1, R2, R3, R4, R5 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or a cyano, nitro or NR6R7 radical,
R6 and R7 representing, independently, a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or also a xe2x80x94COR8 group,
R8 representing a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or NR9R10,
R9 et R10 representing, independently, a hydrogen atom, the OH group, a linear or branched alkyl radical having 1 to 6 carbon atoms;
W does not exist, or represents a bond, or O, S or NR15, in which R15 represents a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms;
xcfx80 represents a hydrogen atom or a protective group of the carbamate type;
R16, R17 and R18 represent, independently, a hydrogen atom or a linear or branched alkyl radical having 1 to 6 carbon atoms;
and m represents an integer from 0 to 6.
A subject of the invention is also, as medicaments, the compounds of general formula (I) described previously or their pharmaceutically acceptable salts. It also relates to pharmaceutical compositions containing these compounds or their pharmaceutically acceptable salts, and the use of these compounds or of their pharmaceutically acceptable salts for producing medicaments intended to inhibit neuronal NO synthase or inductible NO synthase, to inhibit lipidic peroxidation or to provide the double function of NO synthase inhibition and lipidic peroxidation inhibition.
By pharmaceutically acceptable salt is meant in particular addition salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide sulphate, phosphate, diphosphate and nitrate, or of organic acids, such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulphonate, p-toluenesulphonate, pamoate, oxalate and stearate. The salts formed from bases such as sodium or potassium hydroxide also fall within the scope of the present invention, when they can be used. For other examples of pharmaceutically acceptable salts, reference can be made to xe2x80x9cPharmaceutical saltsxe2x80x9d, J. Pharm. Sci. 66:1 (1977).
The pharmaceutical composition can be in the form of a solid, for example powders, granules, tablets, capsules, liposomes or suppositories. Appropriate solid supports can be for example calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.
The pharmaceutical compositions containing a compound of the invention can also be presented in the form of a liquid, for example, solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or the glycols, as well as their mixtures, in varying proportions, in water.
A medicament according to the invention can be administered by topical, oral or parenteral route, by intramuscular injection, etc.
The envisaged administration dose for a medicament according to the invention is comprised between 0.1 mg and 10 g according to the type of active compound used.
In accordance with the invention, the compounds of general formula (I) can be prepared by the process described below.
The compounds of general formula (I) can be prepared from intermediates of general formula (II) according to Diagram 1where A, B, X, Y and "PHgr" are as defined above and Gp is a protective group of carbamate type such as for example the t-butoxycarbonyl group. 
The derivatives of aniline of general formula (II), can be condensed with the compounds of general formula (III), in which L represents a parting group (for example an alkoxy, alkylthio, aralkylthio, sulphonic acid, halide, aryl alcohol or tosyl radical), in order to produce the final compounds of general formula (I) of substituted amidine type (cf. Diagram 1). For example, for B=thiophene, the derivatives of general formula (II) can be condensed with S-methylthiophene thiocarboxamide hydroiodide, prepared according to a method in the literature (Ann. Chim. (1962), 7, 303-337). The condensation can be carried out by heating in an alcohol (for example in methanol or isopropanol), optionally in the presence of DMF and/or pyridine at a temperature preferably comprised between 20 and 100xc2x0 C. for a duration generally comprised between a few hours and overnight.
In the case where B is an amine, the final compounds of general formula (I) are guanidines. These can be prepared, for example, by the condensation of the amines of general formula (II) with the derivatives of general formula (IV) or (IVxe2x80x2). The reagents of general formula (IV) in which L represents, for example, a pyrazole ring are condensed with the amines of general formula (II) according to the conditions described in the literature (J. Org. Chem. (1992) 57, 2497-2502) similarly for the reagents of general formula (IVxe2x80x2) in which L represents, for example, a pyrazole ring and Gp the tBuOCO group (Tetrahedron Lett. (1993) 34 (21), 3389-3392) or when L represents the xe2x80x94Nxe2x80x94SO2xe2x80x94CF3 group and Gp the tBuOCO group (J. Org. Chem. (1998) 63, 3804-3805). During the final stage of the synthesis, deprotection of the guanidine function is carried out in the presence of a strong acid such as for example trifluoroacetic acid.
Therefore the invention also relates to a process for the preparation of a product of general formula (I) as defined previously, characterized in that intermediate of general formula (II)
Axe2x80x94Xxe2x80x94Yxe2x80x94"PHgr"xe2x80x94NH2xe2x80x83xe2x80x83(II)
in which A, B, X, Y and "PHgr" are as defined above,
is reacted with intermediate of general formula (III) 
in which B is as defined above and L represents a parting group, for example an alkoxy, alkylthio, aralkylthio, sulphonic acid, halide, aryl alcohol or tosyl radical.
In addition the invention relates to a process for the preparation of a product of general formula (I) in which B is an amine, characterized in that intermediate of general formula (II)
Axe2x80x94Xxe2x80x94Yxe2x80x94"PHgr"xe2x80x94NH2xe2x80x83xe2x80x83(II)
in which A, B, X, Y and "PHgr" are as defined above is reacted,
a) either with intermediate of general formula (IV) 
xe2x80x83in which L represents a parting group, for example an alkoxy, alkylthio, aralkylthio, sulphonic acid, halide, aryl alcohol or tosyl radical,
b) or with intermediate of general formula (IVxe2x80x2) 
xe2x80x83in which L represents a parting group, for example an alkoxy, alkylthio, aralkylthio, sulphonic acid, halide, aryl alcohol or tosyl radical, and Gp a protective group of carbamate type, for example the t-butoxycarbonyl group,
this reaction being followed, in the case where reaction with the compound of general formula (IVxe2x80x2) is chosen, by hydrolysis in the presence of a strong acid, for example trifluoroacetic acid.
When xe2x80x94Xxe2x80x94Yxe2x80x94"PHgr"xe2x80x94 Represents a Direct Bond:
Intermediates of general formula (II) in the particular case where xe2x80x94Xxe2x80x94Yxe2x80x94"PHgr"xe2x80x94 represents a direct bond are comparable to the compounds of general formula (X), Axe2x80x94NH2, described in the chapter xe2x80x9cSynthesis of intermediatesxe2x80x9d. In this case, these Axe2x80x94NH2 amines can be directly condensed with the derivatives of general formula (III) or (IV) as described in the preceding chapter.
The non-commercial intermediates of general formula (II), are obtained either from detachment of a protective group, or from reduction of a precursor of nitride or nitro type, as illustrated in the synthesis diagrams below.
Deprotection of the Amino Group:
Intermediates of general formula (II), in which A, X, Y and "PHgr" are as defined above, can be prepared from intermediates of general formula (V), Diagram 2, which are compounds comprising a protected amine (Nxe2x95x90Gpxe2x80x2) in the form, for example, of phthalimide or 2,5-dimethylpyrrole. In the case of phthalimides, these are deprotected in a standard fashion using hydrazine hydrate under reflux of ethanol and in the case of pyrroles, deprotection takes place by heating in the presence of hydroxylamine hydrochloride, in order to finally produce to the primary amines of general formula (II). 
Reduction of the Precursors of Azido Type:
The synthetic intermediates of general formula (VI), Diagram 3, in which A, X, Y and "PHgr" are as defined above, are azide derivatives which are converted into a primary amine of general formula (II), for example, using hydrogen in the presence of Pd/C in an appropriate solvent such as ethanol. 
Reduction of the Precursors of Nitro Type:
The reduction of the nitro function of intermediates of general formula (VII), Diagram 4, in which A, X, Y and "PHgr" are as defined above, is generally carried out by catalytic hydrogenation, in ethanol, in the presence of Pd/C, except in the case of molecules sensitive to these conditions where the nitro group is selectively reduced, for example, by heating the product in an appropriate solvent such as ethyl acetate with a little ethanol in the presence of SnCl2 (J. Heterocyclic Chem. (1987), 24, 927-930; Tetrahedron Letters (1984), 25 (8), 839-842), also using SnCl2 in the presence of Zn (Synthesis (1996), (9), 1076-1078), or using NaBH4xe2x80x94BiCl3 (Synth. Com. (1995) 25 (23), 3799-3803) in a solvent such as ethanol, or then by using Raney Ni with hydrazine hydrate added (Monatshefte fxc3xcr Chemie, (1995), 126,725-732; Pharmazie (1993) 48 (11), 817-820) in the case, for example, of the nitrocarbazoles. 
Intermediates of general formula (V), Diagram 5, contain an amine protected in the form of phthalimide, in which X=xe2x80x94Oxe2x80x94, Y=xe2x80x94(CH2)mxe2x80x94 with A, R1, R2, R3, R4, R5, W, m and "PHgr" as defined above, can be prepared from the hydroxylated aromatic rings of general formula (VIII). In the particular case of hydroxycarbazoles, the compounds of general formula (VIII) are prepared according to an experimental protocol in the literature (J. Chem. Soc. (1955), 3475-3477; J. Med. Chem. (1964) 7, 158-161) and in that of hydroxyphenothiazines the protocol is described in J. Med. Chem. (1992) 35, 716. The compounds of general formula (VIII) are condensed with commercial halogenoalkyl-phthalimides in the presence of a base, for example NaH, in a solvent such as DMF, in order to produce intermediates of general formula (V). 
Intermediates of general formula (VI), Diagram 6, in which A, X, Y, R1, R2, R3, R4, R5, W, m and "PHgr" are as defined above, are derivatives of azido type. They are prepared in two stages from intermediates of general formula (VIII) (Diagram 5). The OH radical of the compounds of general formula (VIII) can be alkylated by dihalogenated derivatives of dibromoalkane type, in the presence of a base, for example NaH or NaOH, in order to produce the compounds of general formula (IX) which are then substituted using sodium azide in DMF in order to produce intermediates of general formula (VI). 
The syntheses of the compounds of general formula (VII), which carry a terminal nitro group, in which A, X, Y and "PHgr" are as described above, are illustrated in the following synthesis diagrams.
The carboxamides of general formula (VII), Diagram 7, in which X represents xe2x80x94NR16xe2x80x94COxe2x80x94 and A, Y, "PHgr" and R16 are as defined above, are prepared by condensation of the commercial amines of general formula (X) with the commercial acids of general formula (XI). The carboxamide bonds are formed under the standard conditions of peptide synthesis (M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Verlag, 1984)) in THF, dichloromethane or DMF in the presence of a coupling reagent such as dicyclohexylcarbodiimide (DCC), 1.1xe2x80x2-carbonyldiimidazole (CDI) (J. Med. Chem. (1992), 35 (23), 4464-4472) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC or WSCI) (John Jones, The chemical synthesis of peptides, 54 (Clarendon Press, Oxford, 1991)). The syntheses of the non-commercial amines of general formula (X) and the syntheses of the non-commercial carboxylic acids of general formula (XI) are described in the chapter Preparation of Intermediates. 
The carboxamides of general formula (VII), Diagram 8, in which X represents xe2x80x94COxe2x80x94NR16xe2x80x94 and A, Y, Q, "PHgr", and R16 are as defined above, are prepared by condensation of the commercial acids of general formula (XII) with the commercial amines of general formula (XIII) or the amines of general formula (XIV) under standard conditions for peptide synthesis described previously. The syntheses of the non-commercial acids of general formula (XII) and amines of general formula (XIV) are described in the chapter Preparation of Intermediates. 
The carboxamides of general formula (VII), Diagram 9, in which X represents xe2x80x94Oxe2x80x94, Y represents xe2x80x94(CH2)mxe2x80x94NR18xe2x80x94COxe2x80x94(CH2)nxe2x80x94 with A, R18, m, n and "PHgr" as defined above, are prepared by standard peptide condensation of the acids of general formula (XI) (Diagram 7) with the amines of general formula (II), the syntheses of which have been described in Diagrams 2 and 3. 
The amines of general formula (VII) in which X=xe2x80x94NR16xe2x80x94 and Y=xe2x80x94(CH2)mxe2x80x94 with A, R16, m and "PHgr" as defined above, are prepared, Diagram 10, from the carboxamides of general formula (VII). The reduction of the carboxamide function is carried out in the presence of an excess (5 eq.) of diborane in THF, by heating the mixture to reflux of the solvent in order to produce the amines of general formula (VII). 
The carbamate derivatives of general formula (VII) in which X=xe2x80x94NR16xe2x80x94COxe2x80x94Oxe2x80x94 and Y=xe2x80x94(CH2)mxe2x80x94 with A, m and "PHgr" as defined above, are prepared, Diagram 11, by condensation of an amine of general formula (X) (Diagram 7) with a commercial alcohol of general formula (XV) in the presence of triphosgene and a base such as for example N,N-dimethylaniline in an inert solvent such as, for example, dichloromethane, according to a protocol described in Tetrahedron Lett. (1993) 34 (44), 7129-7132. 
The ureas of general formula (VII) in which X=xe2x80x94NR16xe2x80x94COxe2x80x94NR17xe2x80x94 and Y=xe2x80x94(CH2)mxe2x80x94 or Xxe2x80x94Y=xe2x80x94NR16xe2x80x94COxe2x80x94Qxe2x80x94(in the case of a nitrogenous heterocycle) with A, R17, m, Q and "PHgr" as defined above, are prepared, Diagram 12, from the primary amines of general formula (X) (Diagram 7) and the amines of general formula (XIII) or (XIV) (Diagram 8) in the presence of triphosgene and a tertiary amine, such as, for example, diisopropylethylamine, in a neutral solvent such as dichloromethane (J. Org. Chem. (1994), 59 (7), 1937-1938). 
The carboxylic esters of general formula (VII) in which X=xe2x80x94Oxe2x80x94COxe2x80x94 or xe2x80x94COxe2x80x94Oxe2x80x94 and Y=xe2x80x94(CH2)mxe2x80x94 with A, m and "PHgr" as defined above, are prepared in a single stage from the alcohols of general formula (VIII) (Diagram 5) and the carboxylic acids of general formula (XI) (Diagram 7) or the acids of general formula (XII) (Diagram 8) and the alcohols of general formula (XV) (Diagram 11) in the presence of a coupling agent such as, for example carbonyldiimidazole or dicyclohexylcarbodiimide, in an appropriate solvent such as dichloromethane, for example. 
The ethers of general formula (VII) in which X=xe2x80x94Oxe2x80x94 and Y=xe2x80x94(CH2)mxe2x80x94 with A, m and "PHgr" as defined above, Diagram 14, are prepared in a single stage by condensation of the aromatic alcohols of general formula (VIII) (Diagram 5) and the alcohols of general formula (XV) (Diagram 11) under the standard conditions of Mitsunobu (Synthesis (1981), 1) in the presence, for example, of diethylazodicarboxylate and tributylphosphine, in a solvent such as, for example, THF. 
When X=xe2x80x94Oxe2x80x94, Y is a bond and "PHgr"=phenylene, with A and n as defined above, the ethers of general formula (VII), Diagram 15, can also be prepared in a single stage by condensation of the aromatic alcohols of general formula (VIII) (Diagram 5) with the halogenated derivatives of general formula (XVI), in which Hal represents a halogen atom, in the presence of a base such as, for example, K2CO3, in a polar solvent such as, for example, THF or DMF, at a reaction temperature comprised between 20 and 140xc2x0 C. 
When X=xe2x80x94Oxe2x80x94 and Y=xe2x80x94(CH2)mxe2x80x94Qxe2x80x94(CH2)nxe2x80x94 with A, "PHgr", Q and m as defined above, the ethers of general formula (VII), Diagram 16, can also be prepared by condensation of the aromatic alcohols of general formula (VIII) (Diagram 5) with the halogenated derivatives of general formula (XVII), in which Hal represents a halogen atom, in the presence of a base such as, for example, K2CO3, in an inert solvent such as, for example, CH2Cl2, at a temperature comprised between 40xc2x0 C. and the reflux temperature of the reaction mixture. Synthesis of the compounds of general formula (XVII) is described in the chapter Preparation of Intermediates. 
The amines of general formula (VII), in which X=xe2x80x94NR16xe2x80x94COxe2x80x94 and Y=xe2x80x94(CH2)mxe2x80x94NR18xe2x80x94(CH2)nxe2x80x94 with A, "PHgr", R16, R18, m and n as defined above, are prepared, Diagram 17, by condensation of an aldehyde of general formula (XIX) with an amine of general formula (XVIII) in reducing medium. The reaction is carried out in an alcoholic solvent such as, for example, methanol in the presence of pulverulent 4 xc3x85 molecular sieve, activated beforehand, and of a reducing agent such as, for example, NaBH4 or NaBH3CN. The syntheses of the non-commercial amines of general formula (XVIII) are described in the chapter Preparation of Intermediates. 
In an analogous manner, the amines of general formula (VII), in which X=xe2x80x94CH2xe2x80x94NR16xe2x80x94, with A, Y, "PHgr" and R16 as defined above, are prepared, Diagram 18, by condensation of the aldehydes of general formula (XX) with the amines of general formula (XIII) (Diagram 8) in reducing medium under the conditions described previously. The preparation of the non-commercial aldehydes of general formula (XX) is described in the chapter Preparation of Intermediates. 
Intermediates of general formula (VII), in which A, X, Y, "PHgr", R1, R2, R3, R4 and R5 are as described above, can be subjected to chemical modifications at the level of the A radical, Diagram 19, in particular at the level of the nitrogen atom which can be alkylated using an R11-Hal reagent, as defined above, and in particular using methyl iodide in the presence of a base such as, for example, NaH, in an inert solvent such as THF for example. 
Intermediates of general formula (X) in which A is a diphenylamine (W does not exist), are accessible using the methods described in the literature (Synthesis (1990) 430; Indian J. Chem. (1981) 20B, 611-613; J. Med. Chem. (1975) 18(4), 386-391) which operate through the reduction of a nitrodiphenylamine intermediate. The reduction of the nitro function is carried out in a standard fashion by hydrogenation in the presence of a catalytic quantity of Pd/C in order to access the aminodiphenylamines of general formula (X).
When A is a carbazole derivative (W then represents a direct bond), the preparation methods for the aminocarbazoles of general formula (X) operate through the synthesis of a nitrocarbazole intermediate. These methods are described in Pharmazie (1993) 48(11), 817-820; Synth. Commun. (1994) 24(1), 1-10; J. Org. Chem. (1980) 45, 1493-1496; J. Org. Chem. (1964) 29(8), 2474-2476; Org Prep. Proced. Int. (1981) 13(6), 419-421 or J. Org. Chem. (1963) 28, 884. The reduction of the nitro function of the nitrocarbazole intermediates is, in this case, preferably carried out using hydrazine hydrate in the presence of Raney Nickel.
Intermediates of general formula (X) in which A is a phenothiazine derivative (W represents a sulphur atom), are accessible via methods in the literature which operate through the synthesis of a nitrophenothiazine derivative. In particular 3-nitrophenothiazine is described in J. Org Chem. (1972) 37, 2691. The reduction of the nitro function in order to access the aminophenothiazines of general formula (X) is carried out in a standard fashion by hydrogenation in the presence of a catalytic quantity of Pd/C in a solvent such as ethanol.
The syntheses of the non-commercial acids of general formula (XI), are described in Diagrams 7.1 and 7.2.
In the particular case where Y=xe2x80x94(CH2)mxe2x80x94Qxe2x80x94(CH2)nxe2x80x94 and "PHgr" is a phenylene radical, with Q, m and n as defined above, the carboxylic acids of general formula (XI), Diagram 7.1, are prepared, in 2 stages, from a heterocyclic amine of general formula (XIV) (Diagram 8), for example 4-nitrophenylpiperazine, and of a halogenoester of general formula (XI.1) such as for example ethyl bromoacetate. The condensation is carried out at 20xc2x0 C. in the presence of a base such as, for example, triethylamine in an inert solvent such as, for example, dichloromethane in order to produce intermediates of general formula (XI.2). Saponification by LiOH at 20xc2x0 C. produces the carboxylic acids of general formula (XI).
In the cases where Y=xe2x80x94(CH2)mxe2x80x94Oxe2x80x94(CH2)nxe2x80x94, and "PHgr" is a phenylene radical, with m and n as defined above, the synthesis of the carboxylic acids of general formula (XI), Diagram 7.1, operates through condensation of the halogenated derivatives of general formula (XI.1) on the alcohols of general formula (XI.3) in the presence of a base such as, for example, triethylamine or potassium carbonate, at reflux of a polar solvent such as, for example, THF or DMF. Deprotection of the ester function of intermediate of general formula (XI.4) is then carried out in a standard fashion in the presence of a base or of a strong acid fort in the case of tert-butyl esters. 
The carboxylic acids of general formula (X) in which Y=xe2x80x94(CH2)mxe2x80x94 and "PHgr" represents a substituted phenylene group, with m as defined above, are prepared in 3 stages from the commercial alcohols of general formula (XI.3), Diagram 7.2. Activation of the alcohol is carried out in a standard fashion using methane sulphonyl chloride (MsCl) in the presence of a base such as triethylamine in an inert solvent such as dichloromethane in order to produce intermediates of general formula (XI.4). The mesylate is then displaced by sodium cyanide in DMF in order to produce intermediates of general formula (XI.5). The nitrile function is then hydrolyzed by heating in a mixture of ethanol and concentrated HCl in order to produce the acids of general formula (XI). 
The synthesis of the carboxylic acid derivatives of the phenothiazines of general formula (XII) is described in literature (J. Med. Chem. (1992) 35(4), 716-724).
The non-commercial amines of general formula (XIV) defined previously, in which Q represents homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, are synthesized in three stages from the corresponding commercial diamines. The diamines are selectively mono-protected in the form of carbamate (Synthesis (1984), (12), 1032-1033; Synth. Commun. (1990), 20, (16), 2559-2564) before reacting by nucleophilic substitution with a halogenonitrobenzene, in particular 4-fluoronitrobenzene. The amines, which have been previously protected, are released at the last stage, according to the methods described in the literature (T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Second edition (Wiley-Interscience, 1991)), in order to produce intermediates of general formula (XIV).
The halogenated derivatives of general formula (XVII) defined previously, Diagram 16.1, are accessible in two stages from the amines of general formula (XIII) or (XIV) (Diagram 8) and the commercial halogenated derivatives of general formula (XVII.1). Condensation in order to produce intermediates of general formula (XVII.2) or (XVII.3) is carried out in a standard fashion in the presence of a base such as, for example, K2CO3 in an appropriate inert solvent such as, for example, dichloromethane. Then the alcohol function is activated in the form of a halogenated derivative using, for example, carbon tetrabromide in the presence of triphenylphosphine in order to produce intermediates of general formula (XVII). 
The amines of general formula (XVIII) defined previously, Diagram 17.1, in which A, R16, R18 and m are as defined above, are prepared by condensation of the amines of general formula (X) (Diagram 7) with the protected amino acids (Gp: protective group) of general formula (XVIII.1), under the standard conditions of peptide synthesis (see xe2x80x9csynthesis of carboxamidesxe2x80x9d chapter). Deprotection of the amine of the compounds of general formula (XVIII.2) is then carried out in a standard fashion according to the conditions described in literature (T. W. Greene et P. G. M. Wuts, Protective Groups in Organic Synthesis, Second edition (Wiley-Interscience, 1991)). 
Synthesis of the aldehydes of the phenothiazines of general formula (XX) defined previously is described in literature (J. Chem. Soc. (1951), 1834; Bull. Soc. Chim. Fr. (1969), 1769).
Unless they are defined differently, all the technical and scientific terms used here have the same meaning as that usually understood by an ordinary specialist in the field to which the invention belongs. Similarly, all publications, patent applications, patents and other references mentioned here are incorporated by way of reference.